Introduction

BRCA1-associated protein-1 is a deubiquitinase encoded by the BAP1 tumor suppressor gene. BAP1 mutations have been associated with prognostic implications in renal cell carcinoma, uveal melanoma and mesothelioma. Its role in urothelial carcinoma remains poorly elucidated. We sought to evaluate the prognostic value of BAP1 expression in upper tract urothelial carcinoma (UTUC).

Methods

We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry for BAP1 was performed on tissue microarrays from RNU specimens. BAP1 nuclear staining intensity was graded from 0-3, with positivity defined as average intensity >1. Clinicopathologic characteristics and oncologic outcomes including recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS) were stratified by BAP1 positivity. Prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p<0.05.

Results

373 patients were included for analysis, with median follow-up 36 months. 180 (48.3%) patients were BAP1-negative and 193 (51.7%) were BAP1-positive. While pT stage, lymphovascular invasion (LVI), and pN stage were similar between groups, BAP1 expression was more often associated with sessile architecture, necrosis, and CIS (Table). On multivariable analysis (MVA) adjusted for pT, pN, and LVI, positive BAP1 expression was a significant predictor for worse RFS (HR 1.56, p=0.026) and CSS (HR 1.56, p=0.035). On univariable analysis, BAP1 expression was predictive of worse OS (HR 1.43, p=0.030), though significance was lost on MVA (HR 1.30, p=0.116). KM curves are shown (Figure).

Conclusions

BAP1 expression is associated with adverse pathologic features and worse oncologic outcomes in patients with high-grade UTUC. Although loss of BAP1 is frequently associated with worse outcomes in other malignancies, our findings parallel those of mesothelioma, in which BAP1 loss confers a better prognosis. The role of BAP1 pathways in UTUC pathogenesis remains to be further elucidated.

Funding

none